Potentially fatal interaction between erythromycin and disopyramide

Ragosta, Michael; Weihl, A. C.; Rosenfeld, Lynda E.

doi:10.1016/0002-9343(89)90346-x

Cited by 53 publications

(17 citation statements)

References 8 publications

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“…In recent years, it has been reported that concomitant administration of DP and erythromycin (EM), a macrolide antibiotic, induced Torsades de Pointes (TdP) associated with electrocardiographic QT prolongation. 1,2 In humans, DP is metabolized mainly by the liver into the major metabolite, mono-N-dealkylated disopyramide (MND). 3 Since EM, which is known to inhibit CYP3A4, 4 is reported to inhibit the metabolism of DP, 5 this oxdation enzyme is thought to be from the CYP 3A subfamily, paticularly CYP3A4.…”

Section: Introductionmentioning

confidence: 99%

Pharmacodynamic analysis of the electrocardiographic interaction between disopyramide and erythromycin in rats

Hanada

Ohtani

Kotaki

et al. 1999

Journal of Pharmaceutical Sciences

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Disopyramide (DP) is known to induce QT prolongation and Torsades de Pointes (TdP) when administered concomitantly with erythromycin (EM). To define and evaluate quantitatively the arrhythmogenic risk of the concomitant administration of DP and EM, we investigated the influence of EM on the pharmacokinetics and pharmacodynamics of DP in rats. The time profiles of change in QT interval and plasma concentration of each drug were evaluated during and after constant intravenous infusion of DP (6.0 or 15.0 mg/kg/h), EM (4.0 or 8.0 mg/kg/h), and coadministration of DP and EM (DP 6.0 mg/kg/h plus EM 4.0 mg/kg/h). Each agent induced QT prolongation at plasma concentrations within the therapeutic range in humans. DP-induced QT prolongation was proportional to its plasma concentration. In the case of EM, the Emax model with an "effect compartment" could explain the relationship between plasma EM concentrations and changes in QT interval. Although coadministration of EM with DP gave enhanced QT prolongation compared to dosing with DP alone, EM did not affect the pharmacokinetics of DP. In conclusion, it was shown that a pharmacodynamic interaction contributes to the electrocardiographic adverse reaction (i.e., QT prolongation) induced by coadministration of DP and EM in rats.

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Section: Introductionmentioning

confidence: 99%

Pharmacodynamic analysis of the electrocardiographic interaction between disopyramide and erythromycin in rats

Hanada

Ohtani

Kotaki

et al. 1999

Journal of Pharmaceutical Sciences

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“…6,7) Furthermore, potentially fatal interactions between class 1a antiarrhythmic drugs, disopyramide and erythromycin, and macrolide antibiotics, erythromycin, clarithromycin, and azithromycin, have been reported. [8][9][10][11][12] Erythromycin has been shown to block the rapid component of the delayed rectifier potassium current in guinea pig ventricular myocytes and human cardiac K + channel Kv1.5 at clinically relevant concentrations. 15,16) However, Rubart, et al reported that erythromycin at doses exceeding 20 mg/L prolonged APD both in vitro and in vivo, but the relative rare occurrence of EAD and ventricular arrhythmias suggested that other predisposing factors contribute to the acquired LQTS associated with erythromycin.…”

Section: Discussionmentioning

confidence: 99%

“…6,7) Rogosta, et al reported a potentially fatal interaction between erythromycin and disopyramide, and Nattel, et al reported cross-sensitivity between erythromycin and quinidine. 8,9) In the 1990s, several authors described potentially fatal interactions between class I antiarrhythmic drugs such as disopyramide and quinidine and macrolide antibiotics such as erythromycin, azithromycin, and clarithromycin. [10][11][12] The present study was designed to investigate the combined effect of disopyramide and erythromycin on ventricular action potential duration (APD), the incidence of EAD, and development of ventricular premature contractions (PVCs) and TdP in a canine model of complete atrioventricular block (CAVB).…”

Section: P Olymorphic Ventricular Tachycardia (Pvt) Torsades Dementioning

confidence: 99%

Combined Effect of Disopyramide and Erythromycin on Ventricular Repolarization in Dogs With Complete Atrioventricular Block

et al. 2011

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SummaryThe combined effects of disopyramide (DP) and erythromycin (EM) on ventricular repolarization and the incidences of ventricular premature contractions (VPCs) and torsades de pointes (TdP) were investigated in 12 anesthetized dogs with complete atrioventricular block. Monophasic action potentials (MAPs) were measured from the left and right ventricular (LV and RV) endocardium. The right or left ventricle was paced at a cycle length of 750-1000 msec. Dogs were divided into 2 groups and given either intravenous DP at 3 mg/kg and then intravenous EM at 50 mg/kg (group 1, n = 8), or intravenous EM at 50 mg/kg and then intravenous DP at 3 mg/kg (group 2, n = 4). MAP duration at 90% repolarization (MAPD 90 ) was measured before drug administration (baseline) and again after administration of each drug. RV MAPD 90 and LV MAPD 90 increased significantly (P < 0.02) after administration of each drug in group 1 (RV MAPD 90 : from 247.0 ± 36.3 [baseline] to 283.5 ± 38.3 to 321.8 ± 56.7; LV MAPD 90 : from 262.6 ± 49.1 (baseline) to 296.1 ± 58.8 to 351.0 ± 80.6). Early afterdepolarizations developed in 2 group 1 dogs after administration of DP and in 4 additional dogs after administration of EM. Frequent VPCs occurred in 1 dog after administration of DP and in 2 additional dogs after administration of EM, and TdP and ventricular tachycardias developed in 2 of the 3 dogs after administration of EM. Similar trends occurred in group 2. These results indicate a potentially fatal interaction between DP and EM administered in clinically relevant doses. (Int Heart J 2011; 52: 393-397)

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“…The data presented here, as well as by Daleau et al (1995), suggest a new level for the interaction between these two drugs, that being direct blockade of cardiac K + channels by erythromycin. Direct, additive effects on cardiac K + channels could also underlie the generation of tachyarrhythmias that have been associated with the concurrent administration of erythromycin and disopyramide (Ragosta et al 1989).…”

Section: Discussionmentioning

confidence: 99%

Blockade of the human cardiac K+ channel Kv1.5 by the antibiotic erythromycin

Rampe¹,

Murawsky²

1997

Naunyn-Schmiedeberg's Arch Pharmacol

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Erythromycin administration has been associated with a prolongation of cardiac repolarization in certain clinical settings. This could be due to blockade of voltage-dependent K+ channels in the human heart. For this reason we examined the effects of erythromycin on a rapidly activating delayed rectifier K+ channel (Kv1.5) cloned from human heart and stably expressed in human embryonic kidney cells. When examined using the whole-cell patch clamp technique, erythromycin (100 microM) blocked Kv1.5 current in a time-dependent manner but required prolonged exposure to do so. However, when we examined Kv1.5 current using inside-out macro-patches, erythromycin applied to the cytoplasmic surface rapidly (within 1-2 min) inhibited Kv1.5 current with an IC50 value of 2.6 x 10(-5)M (1.7 - 3.9 x 10(-5)M, 95% C.L.). The main effect of erythromycin was to accelerate the rate of Kv1.5 current decay thereby reducing the current at the end of a prolonged voltage-clamp pulse. Erythromycin also blocked Kv1.5 current in both a voltage- and frequency-dependent manner but had little effect on the activation kinetics, deactivation kinetics, or the steady-state inactivation properties of Kv1.5. These data suggest that erythromycin acts as a blocker of an activated state of the Kv1.5 channel and that it may access its binding site from the intracellular face of the channel. This study is the first to examine the effects of erythromycin on a cloned human cardiac K+ channel. It is concluded that erythromycin blocks Kv1.5 at clinically relevant concentrations. Blockade of voltage-dependent K+ channels in the heart could contribute to the alterations in cardiac repolarization that have been observed with erythromycin.

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Potentially fatal interaction between erythromycin and disopyramide

Cited by 53 publications

References 8 publications

Pharmacodynamic analysis of the electrocardiographic interaction between disopyramide and erythromycin in rats

Pharmacodynamic analysis of the electrocardiographic interaction between disopyramide and erythromycin in rats

Combined Effect of Disopyramide and Erythromycin on Ventricular Repolarization in Dogs With Complete Atrioventricular Block

Blockade of the human cardiac K+ channel Kv1.5 by the antibiotic erythromycin

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